It is well recognized that the photoreceptor synaptic terminal responds to injury and disease by making structural changes. In retinal detachment the rod axon retracts toward the cell body whereas in human and animal retinal degenerations, the photoreceptors grow long neurites or make new synapses with other retinal cells. Whether these changes are harmful or helpful in disease is unknown but these changes do hold out promise that retinal transplantation is possible since they show that photoreceptor synapses are capable of structural plasticity. This application examines the mechanisms involved in synaptic changes in amphibian and mammalian photoreceptor cells and has the following specific aims: 1) to identify the signaling pathways which control axonal plasticity in rod and cone cells; 2) to determine the preferred synaptic targets for photoreceptors and the influence of Muller cells on synaptogenesis; and 3) to translate the results from amphibian photoreceptors to the mammalian retina. Rod and cone photoreceptors will be treated with agonists and antagonists of cyclic nucleotide signaling pathways and examined with immunocytochemistry and confocal laser scanning microscopy to test the hypothesis that rod and cone cells use cAMP- and cGMP-dependent pathways respectively to stimulate structural change. Creation of groups of retinal neurons by micromanipulation with optical tweezers, followed by conventional and video time lapse microscopy will test potential attractive and repulsive forces during the formation of new synapses. And results which demonstrate optimal growth and synapse formation will then be tested on sheets of photoreceptors prepared for transplantation. These projects explore the fundamental mechanisms involved in the plasticity of the photoreceptor synapse after injury and hope to provide a rational basis for future repair of the retina by manipulation of endogenous cellular activities and/or transplantation of neurons.